Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

Takeuchi, Osamu; Hoshino, Katsuaki; Kawai, Taro; Sanjo, Hideki; Takada, Haruhiko; Ogawa, Tomohiko; Takeda, Kiyoshi; Akira, Shizuo

doi:10.1016/s1074-7613(00)80119-3

Cited by 3,029 publications

(2,404 citation statements)

References 45 publications

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“…The bacterial cell envelope components lipopolysaccharide (LPS) and peptidoglycan (PGN) from Gram-negative bacteria have long been known to affect host biology (Cohn and Morse 1960; Hoffmann et al 1999; Kopp and Medzhitov 1999; Takeuchi et al 1999; Medzhitov and Janeway 2000; Kimbrell and Beutler 2001; Koropatnick et al 2004), but neither LPS nor PGN from A. machipongonensis triggered rosette development, alone or in combination (Figure 3A). Instead, we found that A. machipongonensis crude lipid extracts enriched in sphingolipids robustly induced rosette development (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals

Alegado

Brown

Cao

et al. 2012

eLife

229

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Bacterially-produced small molecules exert profound influences on animal health, morphogenesis, and evolution through poorly understood mechanisms. In one of the closest living relatives of animals, the choanoflagellate Salpingoeca rosetta, we find that rosette colony development is induced by the prey bacterium Algoriphagus machipongonensis and its close relatives in the Bacteroidetes phylum. Here we show that a rosette inducing factor (RIF-1) produced by A. machipongonensis belongs to the small class of sulfonolipids, obscure relatives of the better known sphingolipids that play important roles in signal transmission in plants, animals, and fungi. RIF-1 has extraordinary potency (femtomolar, or 10−15 M) and S. rosetta can respond to it over a broad dynamic range—nine orders of magnitude. This study provides a prototypical example of bacterial sulfonolipids triggering eukaryotic morphogenesis and suggests molecular mechanisms through which bacteria may have contributed to the evolution of animals.DOI: http://dx.doi.org/10.7554/eLife.00013.001

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Section: Resultsmentioning

confidence: 99%

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals

Alegado

Brown

Cao

et al. 2012

eLife

229

242

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“…TLR2-deficient C57BL/6 mice [33] were backcrossed ten generations to NOD/Caj mice and intercrossed to generate TLR2-deficient homozygous NOD mice [34]. Female C57BL/6 mice were purchased from Charles River Laboratories.…”

Section: Micementioning

confidence: 99%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansonisoluble egg antigen (SEA) can induce, together with a Th2 response, TGF-b-dependent Foxp3 expression in naïve CD4 1 T cells from NOD mice. We found that SEA can directly upregulate the expression of surface-bound TGF-b in purified CD4 1 T cells in the absence of accessory cell interactions. In this study, we show that the C-type lectin receptors DEC-205 and galectin-3 were involved in the direct interaction between S. mansoni antigens and CD4 1 T cells. SEA was able to enhance CD4 1 T-cell secretion of bioactive TGF-b in response to TLR2 ligand stimulation, in the absence of APC. We also show that TLR2 expressed on CD4 1 T cells was important for the Foxp3 expression induced by SEA.

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“…Tlr4 -/- [45], Tlr2 -/- [46], Myd88 -/- [30] and Tirap -/- [29] mice were generated in the C57BL/6 mouse background, and Trif -/- [47] and Tram -/-[48] mice were generated in the C57BL/6/129 mouse background and were made in the BIKEN animal facilities (Osaka, Japan). Lps2, a non-functional codominant allele of Trif, was induced by N-ethyl-N-nitrosourea mutagenesis on a pure C57BL/6 mouse background [49] in the Scripps Institute animal facilities (La Jolla CA).…”

Section: Mouse Strainsmentioning

confidence: 99%

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-b (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif -/-and Tram -/-mice remained infected with P fimbriated E. coli but cleared thetype 1 fimbriated strain, while Myd88 -/-mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 may be engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands. IntroductionToll-like receptors (TLR) control the innate host defence at mucosal surfaces and yet commensals do not induce an inflammatory response at those sites. The relative inertia to the commensals is paradoxical, as the TLR recognise conserved pathogen-associated molecular patterns (PAMP), which are present on both pathogenic and commensal bacteria. Lipolysaccharide (LPS), flagellin, peptidoglycan or DNA may bind directly to the TLR but in addition, co-receptors are needed to enhance the TLR response to these conserved ligands [1][2][3]. Myeloid cells use CD14 and MD-2 as co-receptors for LPS in TLR4 signalling, and minute amounts of LPS may elicit a strong systemic inflammatory response [4,5]. However, the TLR response to pathogen attack at mucosal surfaces is controlled by different interactions. Epithelial cells must be protected from constant TLR activation by commensals and their PAMP, in order for mucosal integrity to be maintained. The epithelial cells thus lack co-receptors like CD14 [6][7][8][9][10][11], and in addition, commensals have been suggested to actively suppress epithelia responses through NF-jB [12,13]. Yet, mucosal pathogens evoke rapid TLR4-dependent responses at mucosal sites, suggesting that alternative ligands and receptors might be involved in mucosal TLR activation. Pathogens use adhesive surface ligands to break the inertia of the mucosal barrier [14][15][16]. The innate defence is activated as a direct result of these interactions and epithelial cells produce the first wave of me...

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Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

Cited by 3,029 publications

References 45 publications

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals

A bacterial sulfonolipid triggers multicellular development in the closest living relatives of animals

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

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